We have demonstrated several new observations regarding the role of B cells in HIV-1 immunopathogenesis. Following our seminal observation that replication-competent HIV-1 circulates on B cells in vivo through interactions involving complement fragments on virions and CD21 on B cells, we began a detailed study of the causes and consequences of these interactions. One consequence of HIV-B cell binding events is that B cells contribute to the trafficking of virus between peripheral blood and lymphoid tissues. Using phylogenetic analyses of virus found on B cells and virus found in CD4+ T cells of peripheral blood and lymph nodes, as well as in the plasma of HIV-infected viremic patients, we established that B cells participate in HIV dissemination through these various compartments. We have also observed that CD21 expression was reduced on B cells of viremic patients. We have further investigated this phenomenon by using quantitative flow cytometry and mRNA measurements to demonstrate that CD21 expression was significantly reduced during viremia and significantly upregulated to normal levels following suppression of viremia. We also conducted longitudinal analyses of B cell function on several chronically infected patients, before and after reduction of viral load by anti-retroviral therapy. High viral load was clearly associated with a reduction in B cell function, as measured by proliferation in vitro in response to a variety of B cell stimuli. The highest degree of dysfunction was observed in response to B cell receptor stimulation, similar to what may occur in vivo when B cells encounter antigen or other immune cells involved in antigenic responses, such as CD4+ T cells. Furthermore, we observed strikingly dichotomous effects when B cells of viremic patients were separated into two sub-populations; one expressing low levels of CD21 and one expressing high levels of CD21. CD21low B cells, while demonstrating profoundly reduced levels of proliferation in response to B cell stimuli, were found to spontaneously secrete high levels of immunoglobulins (Ig) when compared to their CD21high counterpart. This observation led us to speculate that the CD21low B cells of viremic patients were related to terminally differentiated Ig-secreting B cells, called plasma cells, that are generally absent from the peripheral blood of healthy individuals yet have been observed in certain inflammatory and neoplastic diseases. By using electron microscopy to look at B cell morphology, we observed that cells with typical plasma cell features were enriched in the CD21low B cell fraction of HIV-infected viremic patients and were absent from their corresponding CD21high B cell fraction. These findings indicate that HIV viremia coincides with the appearance of highly dysfunctional B cells. In addition, these observations offer new insights into the mechanisms of the defects of the humoral immune responses known to be present in HIV-infected individuals.